1. Field of the Invention
The present invention relates generally to formulations comprising paracetamol. More particularly, the present invention provides a swallow formulation comprising paracetamol which facilitates the rapid delivery of paracetamol into the circulatory system following oral administration. The present invention further relates to methods for inducing efficient pain relief including an analgesic effect by the administration of the paracetamol formulation.
2. Description of the Prior Art
Bibliographic details of the publications referred to in this specification are also collected at the end of the description.
Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.
Paracetamol, also known as N-acetyl-p-aminophenol, acetaminophen and APAP, is an analgesic and antipyretic agent and is widely used in prescription and non-prescription medicines. Paracetamol was first marketed in the 1950's and is now a commonly used agent (Prescott Am. J. Ther. 7(2):143-147 2000). The precise mechanism of paracetamol's analgesic and antipyretic effect remains unclear. However, some studies have suggested that the rate of administration is a factor (Nielsen et al. Eur. J. Clin. Pharmacol. 42(3): 261-264, 1992, Luthy, et al. Schweiz Med. Wochenschr 123 (Suppl 50)/II:406, 1993). Accordingly, increasing the rate of absorption of paracetamol should enable a greater and more rapid analgesic effect after oral dosing. In this regard, oral delivery is the most convenient and acceptable route of drug administration to end users, especially for a drug administered at high doses and frequency, such as paracetamol.
Improving the rate and extent of absorption of oral formulations of compounds has been the subject of substantial research. In general, once a solid swallow composition reaches the stomach, it undergoes disintegration and/or dissolution and passes into the small intestine where the active ingredient is absorbed across intestinal walls into the circulatory system via the portal vein and liver before reaching the site of action.
Rates of absorption are often assessed by comparing standard pharmacokinetic parameters such as the time to peak plasma concentration (Tmax) and the peak plasma concentration (Cmax). The extent of absorption is assessed by the area under the plasma concentration-time curve (AUC). A short Tmax has been used to indicate rapid absorption. The FDA Guidance for Industry on Bioavailability and Bioequivalence Studies for Orally Administered Products (2003) and related publications (Chen et al, Clin. Pharmacokinet. 40(8):565-72, 2001) recommend the use of partial AUC as an early exposure measure, such that a high partial AUC will be an indicator of rapid absorption. The parameters for known formulations vary greatly between subjects. The parameters also vary depending on aspects of the study protocol such as the sampling scheduling, subject posture and general subject health. Values quoted in this specification are given as mean±standard deviation unless otherwise noted.
For paracetamol tablets supplied by McNeil, a Tmax value has been quoted as 45.6 minutes with a standard error of 7.2 minutes with a corresponding Cmax value of 11.99 mg·L−1 with a standard error of 1.02 (Ameer et al., J. Pharm. Sci, 72:955-958, 1983)). Other values quoted include a Tmax of 35.6±27.7 minutes and Cmax of 9.47±4.18 mg·L−1 (Rumble et al., Clin. Pharmacokinet. 20 (2): 167-173, 1991), a Tmax of 1.82 hours with a standard error of 0.46 hours and a Cmax of 20.4±3.2 mg·L−1 for Paralen tablets and for Panadol tablets, a Tmax of 35 minutes and as high as 77 minutes and a Cmax value of 17.02±6.04 mg·L−1 (Grattan et al., Eur. J Pharm. Biopharm. 49(3):225-229, 2000).
The range of paracetamol plasma concentrations for e effective analgesia in humans is quoted to be about 5-20 μg·mL−1. (Prescott, Medical Clinics of North America, 58:907-916, 1974). For antipyresis a paracetamol concentration of 10-20 μg·mL−1 has been shown to be effective (Rumack et al, Pediatrics 62(Suppl):898-903, 1978).
In a submission compiled by McNeil in 2002 in relation to Tylenol to demonstrate safety and efficacy of paracetamol to the United States Food and Drug Administration (USFDA), the effective concentration which elicits 50% of the maximum drug response (EC50) was estimated to be between 15.2 μg·mL−1 and 16.55 μg·mL−1 (McNeil submission to FDA, 2002)
Prescott (1974, supra) reported there may be as much as an 80-fold range in concentrations 1 hour after therapeutic doses of paracetamol were administered in 43 patients. He concluded that pharmacokinetic variability impacts on response rates for analgesics. In fact, many patients may never achieve a therapeutic effect.
In U.S. Pat. No. 6,316,025, Grattan describes a swallow tablet of paracetamol containing 300 mg to 1000 mg of sodium bicarbonate per tablet and a paracetamol to sodium bicarbonate ratio of between 0.74 and 1. Grattan et al. (2000 supra) subsequently reported that a formulation with 630 mg sodium bicarbonate gave a Tmax of 17.5±4.95 minutes and a Cmax of 29.79±9.06 mg·L−1. It was suggested that this was due to an osmotic effect of sodium bicarbonate, which would be isotonic when ingested with 100 mL of water.
US Patent Application No. 20040204475 describes a formulation containing sodium bicarbonate and eletriptan. The sodium bicarbonate is administered in an amount to obtain a duodenal concentration approximately isotonic with serum (150 mmol). The formulations exemplified all contained 630 mg sodium bicarbonate.
US Patent Application No. 20040170681 describes a paracetamol formulation containing less than 100 mg sodium bicarbonate per tablet. About 90% of the paracetamol is described as being released from this formulation in 15 minutes using United States Pharmacopoeia (USP) dissolution apparatus 2 with 900 mL 0.05 N hydrochloric acid at 30 rpm and 37° C. A formulation was exemplified which resulted in an area under the plasma concentration-time curve at 20 minutes after administration (AUC20) of 17 μg·min·mL−1 in fed subjects when given as a 1000 mg paracetamol dose.
United Kingdom Patent No. 2103087 describes the use of antacids in paracetamol tablets. Antacids including calcium carbonate and sodium bicarbonate were used in the range of 60-1200 mg. The greatest increase was noted with 225 mg of sodium bicarbonate which showed an increase in the rate of absorption of paracetamol of between 7% and 31% compared with conventional paracetamol tablets. The shortest Tmax reported was 29 minutes.
In accordance with the present invention, paracetamol formulations and in particular swallow formulations are defined in which the parameters for drug dissolution and absorption have been significantly improved.